Can intramuscular ceftriaxone replace benzathine penicillin G for treating recent primary, secondary, or early latent syphilis, especially in pregnant or penicillin‑allergic patients?

Can IM Ceftriaxone Replace Benzathine Penicillin G for Syphilis?

No—benzathine penicillin G remains the definitive first-line treatment for all stages of syphilis, and ceftriaxone should only be considered as a second-line alternative in carefully selected non-pregnant, penicillin-allergic patients when desensitization is not feasible. 1

Why Penicillin Remains the Gold Standard

• Benzathine penicillin G is supported by more than 40 years of clinical experience and achieves 90–100% treatment success for primary, secondary, and early latent syphilis with a single 2.4 million unit IM dose. 2, 1
• Penicillin is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection, making it absolutely mandatory in pregnancy. 2, 1
• The CDC explicitly states that parenteral penicillin G is the preferred drug for all stages of syphilis, with preparation, dosage, and duration determined by disease stage. 1

When Ceftriaxone May Be Considered

Non-Pregnant, Penicillin-Allergic Patients

Ceftriaxone 1 gram IM or IV daily for 10–14 days is a reasonable alternative for early syphilis (primary, secondary, or early latent) based on randomized trial data showing comparable efficacy to benzathine penicillin. 1, 3

• A 2017 multicenter Chinese trial demonstrated that ceftriaxone 1 gram IV daily for 10 days achieved a 90.2% serologic response at 6 months versus 78.0% with benzathine penicillin (p=0.01), with particularly strong results in secondary syphilis (95.8% vs 76.2%, p<0.01). 3
• The CDC acknowledges that limited clinical studies, along with biological and pharmacologic considerations, suggest ceftriaxone should be effective for early-stage syphilis, though proper dose and duration have not been definitively established. 2

Critical Limitations and Contraindications

Ceftriaxone is absolutely contraindicated in pregnancy—all pregnant patients with penicillin allergy must undergo desensitization followed by penicillin therapy, with no exceptions. 2, 1, 4

• Although one 2005 case series reported successful use of ceftriaxone 250 mg IM daily for 7–10 days in 11 pregnant women with penicillin allergy 5, and a 2022 case report described prevention of congenital syphilis using ceftriaxone in a woman with Stevens-Johnson syndrome to penicillin 6, these isolated reports do not override the CDC's absolute requirement for penicillin desensitization in pregnancy. 1
• Erythromycin, tetracyclines, azithromycin, and ceftriaxone are inadequate alternatives because they do not reliably cure fetal infection. 1

Specific Ceftriaxone Regimens by Disease Stage

Early Syphilis (Primary, Secondary, Early Latent)

• Dose: 1 gram IM or IV daily for 10–14 days 1, 3
• Evidence quality: Moderate—supported by one well-designed randomized trial 3 and CDC acknowledgment of biological plausibility 2

Late Latent Syphilis

• Evidence is extremely limited for ceftriaxone in late latent disease 1
• The preferred alternative for penicillin-allergic patients remains doxycycline 100 mg orally twice daily for 28 days 1, 4

Neurosyphilis

• Ceftriaxone 2 grams IV (not IM) daily for 10–14 days may be considered when penicillin desensitization is not feasible, but supporting data are very limited 1
• Aqueous crystalline penicillin G 18–24 million units IV daily for 10–14 days remains the definitive treatment 1

Critical Safety Considerations

Cross-Reactivity Risk

Patients with severe penicillin allergy (Stevens-Johnson syndrome, anaphylaxis) may also react to ceftriaxone because both are beta-lactam antibiotics. 1

Mandatory Pre-Treatment Steps

• CSF examination must exclude neurosyphilis before using any non-penicillin regimen for late latent syphilis or syphilis of unknown duration 1, 4
• All patients with syphilis should be tested for HIV at diagnosis, as co-infection influences monitoring intensity 1

Follow-Up Requirements for Ceftriaxone-Treated Patients

More intensive monitoring is required due to limited long-term efficacy data compared with penicillin:

• Perform quantitative nontreponemal tests (RPR or VDRL) at 3,6,9,12, and 24 months after treatment 1
• A fourfold decline in titer within 6 months is expected for early syphilis 1
• Treatment failure is defined as persistent or rising titers, or failure of an initially high titer (≥1:32) to decline fourfold within 6–12 months 1, 4

Why Azithromycin Should Never Be Used

Azithromycin is absolutely contraindicated in the United States due to widespread macrolide resistance and documented treatment failures, despite some evidence of efficacy in low-resistance areas. 1, 7

Algorithm for Deciding Between Penicillin and Ceftriaxone

1. Is the patient pregnant?

   • Yes → Penicillin desensitization is mandatory; ceftriaxone is never acceptable 1
   • No → Proceed to step 2

2. Does the patient have a documented penicillin allergy?

   • No → Use benzathine penicillin G (standard regimen) 1
   • Yes → Proceed to step 3

3. Is penicillin desensitization feasible?

   • Yes → Desensitize and use penicillin 1
   • No → Proceed to step 4

4. What is the disease stage?

   • Early syphilis (primary, secondary, early latent) → Ceftriaxone 1 g IM/IV daily × 10–14 days 1, 3
   • Late latent syphilis → Doxycycline 100 mg PO BID × 28 days (preferred); ceftriaxone has insufficient data 1, 4
   • Neurosyphilis → Ceftriaxone 2 g IV daily × 10–14 days (very limited data) 1

5. Has neurosyphilis been excluded?

   • No → Perform CSF examination before any non-penicillin regimen 1, 4
   • Yes → Proceed with chosen alternative regimen

Common Pitfalls to Avoid

• Never use ceftriaxone in pregnancy under any circumstances—desensitization to penicillin is mandatory 1
• Never assume ceftriaxone is safe in patients with severe penicillin allergy (e.g., Stevens-Johnson syndrome)—cross-reactivity is possible 1
• Never skip the CSF examination before treating late latent syphilis with ceftriaxone, as undiagnosed neurosyphilis will not respond to non-IV therapy 1, 4
• Never shorten the 10–14 day ceftriaxone course—single-dose ceftriaxone is ineffective 2
• Never use oral penicillin preparations for any stage of syphilis—they are ineffective 1